Sustained release of methantheline

ABSTRACT

A sustained release pharmaceutical composition which includes methantheline bromide and a polymer of a monomer mixture of a monoester of acrylic acid and/or methacrylic acid and a polyhydric alcohol; and divinyl benzene.

United States Patent Sim et al. Sept. 16, 1975 SUSTAINED RELEASE OF [56]References Cited METHANTHEUNE UNITED STATES PATENTS [75] Inv n or Jam Y-im; M ri H- V n 3,577,512 5/1971 Shepherd et al 424/21 Horn; Arthur 1.Cohen; Stanley E. Gordesky; Stanley I. Gordon, all of Rochester, NY.

Assignee: Union Corporation, Verona, Pa.

Filed: Sept. 10, 1973 Appl. No.: 395,862

Primary ExaminerShep K. Rose Attorney, Agent, or FirmPollock, Philpitt &Vande Sande 5 7 ABSTRACT A sustained release pharmaceutical compositionwhich includes methantheline bromide and a polymer of a monomer mixtureof a monoester of acrylic acid and/or methacrylic acid and a polyhydricalcohol; and divinyl benzene.

1 Claim, No Drawings SUSTAINED RELEASE OF METHANTHELINE BAC KGROUND OFTHE INVENTION The present invention is concerned with a sustainedrelease pharmaceutical composition, and in particular is concerned witha sustained release pharmaceutical composition which contains awater-insoluble but water-swellable hydrophilic polymer of a monomericmixture containing a monoester of acrylic and/or methacrylic acid; anddivinyl benzene.

It has previously been suggested to incorporate drugs into hydrophilicpolymers to provide sustained release of the drug. Although a widevariety of suitable polymers and applicable drugs have previously beensuggested, only a very limited number of combinations of particulardrugs and particular polymers have to date been successful in providingsustained release characteristics. In addition, various combinationswhich provide sustained release require mixtures of substituents incombination with the drug.

It has become quite evident that not any combination of any drug and anyhydrophilic polymer will provide a sustained release pharmaceuticalcomposition. The preparation of sustained release pharmaceuticalcompositions from only a polymer and a drug is highly empirical. The arthas not advanced to the stage where a person skilled in the art canpredict whether a particular combination of a drug and hydrophilicpolymer will produce a sustained release pharmaceutical composition.

Accordingly, it is an object of the present invention to provide asuitable sustained release pharmaceutical composition. It is a furtherobject of the present invention to provide a sustained releasepharmaceutical composition which requires only the pharmacologicalmaterial and the hydrophilic polymer and does not require the presenceof auxiliary constituents.

SUMMARY OF THE INVENTION The present invention is concerned with asustained release pharmaceutical composition comprising:

A. a matrix of a water-insoluble but water-swellable hydrophilic polymerof a monomer mixture contaming:

l polymerizable monoester of acrylic and/or methacrylic acid and apolyhydric alcohol; and 2. divinyl benzene; and wherein the monomermixture contains from about 90 to about 99.9% by weight of l and fromabout 0.I to about l% by weight of (2) based upon the total weight of l)and (2) in the monomer mixture; and

B. methantheline bromide in an amount sufficient for the total dosagerequirement during a treatment period; and being entrapped in saidmatrix.

DESCRIPTION OF PREFERRED EMBODIMENTS The polymerizable monoesters whichare suitable in obtaining the polymers employed in the present inventionmust be water-miscible. Such polymerizable monoesters are monoesters ofeither acrylic and/or methacrylic acid and a polyhydric alcohol andpreferably a dihydric alcohol. Suitable dihydric alcohols which may beemployed to form the esters used in the present invention include amongothers ethylene glycol, 1,3- propanediol, the dialkylene glycols such asdiethylene glycol and dipropylenc glycol; and the polyalkylene glycolssuch as polyethylene glycol and polypropylene glycol; 1,6-hexamethyleneglycol; and 1,4-butanediol. Some suitable polyhydric alcohols whichcontain from O to 6 to alcohol groups and which may be employed to formthe ester used in the present invention include glycerol, trimethylolpropane, trimethylolethane, pentaerythritol, and hexitols such asmannitol and sorbitol. Examples of some suitable polymerizablemonoesters include 2-hydroxy ethyl methacrylate, Z-hydroxy ethylacrylate, 2-hydroxy propyl methacrylate, diethylene glycolmonomethacrylate, diethylene glycol monoacrylate, Z-hydroxy propylacrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate,dipropylene glycol monomethacrylate, glyceryl methacrylate, andpentaerythritol methacrylate, with the preferred polymerizable monoesterbeing Z-hydroxy ethyl methacrylate. The amount of polymerizablemonoester employed in the monomeric mixture to prepare the polymers ofthe present invention is usually from about to about 99.9% by weight,and is preferably from about to about 99.8% by weight, based upon thetotal weight of the polymerizable monoester, and divinyl benzene. Themost preferred amount of monoester is about 99.5% by weight based uponthe total weight of the monoester and divinyl benzene.

The divinyl benzene employed in preparing the polymers used in thepresent invention is usually present in amounts from about 0.1 to 10% byweight. The preferred amount of divinyl benzene is between about 0.2 andabout 5% by weight, and the most preferred amount is about 0.5% byweight.

Methantheline bromide, which is the drug employed according to thepresent invention, is generally used in amounts of about 0.1 to about50%, preferably from about 0.5 to about 35% and most preferably fromabout I to about 30% by weight based upon the total weight of themethantheline bromide and the waterinsoluble but water-swellablehydrophilic polymer. The water-insoluble but water-swellable hydrophilicpolymer is generally employed in amounts of about 50 to about 99.9%,preferably from about 65 to about 99.5% by weight, and most preferablyfrom about 70 to about 99% by weight based upon the total weight of themethantheline bromide and water-insoluble but waterswellable hydrophilicpolymer.

In addition, the pharmaceutical compositions of the present inventioncan include such other materials as plasticizers, inert fillers, andsuspending aids such as Cab-O-Sil and bentone for the methanthelinebromide.

Moreover, the compositions of the present invention can be furtherencapsulated by another polymeric or other film-forming substanceaccording to particular applications of the composition. Such auxiliaryencapsulating layers can be soluble or insoluble in aqueous medium, thesolubility or swelling being dependent or independent of pH and/or ionicstrength, and can be susceptible or non-susceptible to enzymatic action.

The pharmaceutical compositions of the present invention can be preparedby admixing the methantheline bromide or an aqueous solution thereof andthe monomeric mixture containing the polymerizable monoester, anddivinyl benzene; and then by polymerizing to provide a matrix of thewater-insoluble but water-swellable polymer entrapping the methanthelinebromide. The pharmaceutical compositions of the present invention canalso be prepared by contacting the methantheline bromide with thewater-insoluble but water-swellable polymer such as by immersing thepolymer in a bath such as an aqueous bath of the drug to cause diffusionof the methantheline bromide into the polymer matrix. Generally themethantheline bromide is contacted with the polymer for at least about15 minutes to cause diffusion into the polymer matrix. Of course, thiscan vary greatly depending upon the relative amounts of the ingredients.

The waterswellable polymers employed in the present invention generallycan be prepared by employing bulk polymerization techniques. The termbulk polymerization as used herein includes those polymerizationscarried out in the absence of a solvent or dispersing liquid as well asthose polymerizations carried out in the presence of water orwater-soluble or polymer-soluble liquid swelling agents in such amountsas not to significantly alter the nature of the polymerization process.

The polymerization catalyst employed can be any of the catalysts whichare suitable in polymerizing compounds containing ethylenic unsaturationand preferably are the free radical catalysts. Of particular interestare the peroxide catalysts. Some examples of suitable peroxide catalystsinclude hydrogen peroxide, benzoyl peroxide, tertbutyl peroctoatc,phthalic peroxide, succinic peroxide, benzoyl acetic peroxide, tertbutylperoxy pivalate, coconut oil acid peroxide, lauric peroxide, stearicperoxide, oleic peroxide, tert-butyl hydroperoxide, tetralinehydroperoxide, tert-butyi diperphthalate, curnene hydroperoxide,tert-butyl pebenzoate, acetyl peroxide, 2,4-diehlorobenzoyl peroxide,urea peroxide, caprylyl peroxide. p chlorobenzoyi peroxide, ditert-butylperoxide, 2,2-bis(tert-butyl peroxy)butane, hydroxyheptyl peroxide, thediperoxide of benzaldehyde; alkylperoxycarbonates such asdiisobutylperoxy bicarbonate, di-secondary butyl peroxy bicarbonate, andtertbutyl peroxyisopropylcarbonate, and the like. The preferred catalystis one of which is effective at moderately low temperatures such as atabout 30-90 C.

The amount of catalyst employed depends upon the type of catalyst systemused and is generally from about 0.01 to about 10 parts by weight per Iparts of the monomer mixture, and preferably is from about 0.1 to abouti part by weight per 100 parts of the monomer mixture.

The polymerization is generally carried out at ten1 peratures from aboutroom temperature to about l50 C. lt is generally preferred to initiatethe polymerization at relatively low temperatures such as from about 35to about 85 C and then to increase the temperature to about 90 to aboutl50 C as the reaction proceeds and preferably after most of the reactionhas been completed. The most preferred initial temperature range ofpolymerization is between about 30 and 90 C.

Usually the polymerization is conducted under autogenous pressure in aclosed reaction vessel. However, any suitable means to preventsignificant evaporation of any of the monomers can be employed.

Generally, the polymerization is completed in about onehulf to aboutl2hours and preferably is completed in about 4 to about 6 hours. It isunderstood, of course, that the time and temperature are inverselyrelated. That is, temperatures employed at the upper end of thetemperature range will provide polymerization pro- Cesses wh ch can becompleted near the lower end of the time range.

In addition, it may be desirable for the copolymers obtained from suchpolymerizations to be post cured at temperatures somewhat higher thanthose initially employed in the polymerization. Usually the temperaturesemployed in the post cure will range from about to about 150 C. Twohours is usually more than sufficient for such a post curing operation.Preferably the post cure is completed in 2 to 4 hours.

The pharmaceutical compositions of the present invention can be utilizedfor oral ingestion, implantation, or application a mucous membrane. Thepharmaceutical compositions of the present invention can be implantedsubcutaneously, constitute a part of a prosthesis, or be inserted in acavity of the human body. Upon application to the desired part of thebody by the desired mode, the pharmaceutical compositions of the presentinvention provide sustained release of the pharmacological material bydiffusion through pores of the water-insoluble but water-swellablepolymeric matrix to the desired part of the body upon contact with bodyfluids.

The present invention makes it possible to obtain a sustained releasepharmaceutical composition which requires only the drug and thewater-insoluble but waterswellable polymer and does not require thepresence of auxiliary constituents. In addition, the sustained releasecharacteristics of the present invention could not be predictedparticularly since the polymers employed in this invention did notalways provide sustained release compositions. Moreover, whenmethantheline bromide is employed together with other poly mers, asustained release composition is not always obtained.

The following example is presented to further illustrate the presentinvention. All parts are by weight unless the contrary is stated.

EXAMPLE 1 A polymeric composition is prepared by admixing about l97.2parts of Z-hydroxy ethyl methacrylate; about 2 parts of diviny] benzene;and about 0.8 parts of tertbutyl peroctoate. The mixture is heated fromabout room temperature to about 70 C in 4 hours and then maintained at70 C for about 8 hours under a nitrogen atmosphere to effectpolymerization. The mixture is post cured by heating under atmosphericpressure at C for 2 hours. About 155.2 parts of the resulting polymericcomposition are soaked for about 12 hours at ambient temperature inabout 5000 parts of isotonic saline solution (0.9% NaCl) containing I00mg of methantheline bromide per 5 ml of saline solution (0.9% NaCl). Theabove composition is introduced into a beaker containing 20 millilitersof isotonic saline solution (0.9% NaCl) and the beaker is shaken at aconstant temperature of 37 C in a thermostatic water bath shaker. Thecomposition is eluted for 3 hours, dried and then replaced in the beakerand re-eluted. The concentration of eluted methantheline is determinedwith a Beckman DB-GT spectrophotometer using the maximum absorption ofmethantheline bromide at 282 nanometers. Elution rates are checked afterthe initial 3-hour elution period shown below and fresh isotonic salinesolution is employed after each reading. The results are listed below.

What is claimed is: l. A sustained release oral ingestion 33 hourmethantheline eluting pharmaceutical composition comprising:

A. polymerized and cured matrix of water-insoluble but water-swellablehydrophilic polymer of a monomer mixture containing:

l. Z-hydroxyethyl methacrylate; and

2. divinyl benzene wherein said monomer mixture contains about 197.2parts by weight of l) per about 2 parts by weight of (2); and

B. said polymerized and cured matrix having been soaked for about 12hours in isotonic saline solution containing per 5 ml of isotonic salinesolution at least about mg of methantheline bromide in an amountsufficient for the total dosage requirement adapted to gradually elutemethantheline upon oral ingestion during 33 hours of a treatment period;and thereby the methantheline bromide being entrapped in said matrix.

l I l i i

1. A SUSTAINED RELEASE ORAL INGESTION 33 HOUR METHANTHELINE ELUTINGPHARMACEUTICAL COMPOSITION COMPRISING: A. POLYMERIZED AND CURED MATRIXOF WATER-INSOLUBLE BUT WATER-SWELLABLE HYDROPHILIC POLYMER OF A MONOMERMIXTURE CONTAINING:
 1. 2-HYDROXYETHYL METHACRYLATE, AND
 2. DIVINYLBENZENE WHEREIN SAID MONOMER MIXTURE CONTAINS ABOUT 197.2 PARTS BYWEIGHT OF (1) PER ABOUT 2 PARTS BY WEIGHT OF (2), AND B. SAIDPOLYMERIZED AND CURED MATRIX HAVING BEEN SOAKED FOR ABOUT 12 HOURS INISOTONIC SALINE SOLUTION CONTAINING PER 5 ML OF ISOTONIC SALINE SOLUTIONAT LEAST ABOUT 100 MG OF METHANTHELINE BROMIDE IN AN AMOUNT SUFFICIENTFOR THE TOTAL DOSAGE REQUIREMENT ADAPTED TO GRADUALLY ELUTEMETHANTHELINE UPON ORAL INGESTION DUING 33 HOURS OF A TREATMENT PERIOD,AND THEREBY THE METHANTHELINE BROMIDE BEING ENTRAPPED IN SAID MATRIX. 2.divinyl benzene wherein said monomer mixture contains about 197.2 partsby weight of (1) per about 2 parts by weight of (2); and B. saidpolymerized and cured matrix having been soaked for about 12 hours inisotonic saline solution containing per 5 ml of isotonic saline solutionat least about 100 mg of methantheline bromide in an amount sufficientfor the total dosage requirement adapted to gradually elutemethantheline upon oral ingestion during 33 hours of a treatment period;and thereby the methantheline bromide being entrapped in said matrix.